This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. In every living organism, protein synthesis is catalyzed by a large, dynamic RNA-protein macromolecular machine called the ribosome. This 2.5 million Dalton enzyme is comprised of two asymmetric subunits that promote messenger RNA-directed translation of the genetic code. Our laboratory is interested in the structural basis for how protein synthesis is regulated via protein-protein and protein-RNA interactions. One problem we are interested in is how the ribosome performs both programmed and error-inducing mRNA frameshifts. Our recent structural work shows that frameshifts tRNAs promote non-canonical anticodon-codon pairing in the A site and we aim to expand these studies to different modified tRNAs after peptide bond formation in the P site. Understanding the detailed mechanism of how the ribosome is regulated is important not only because translation is a fundamental biological process in all cells, but also because many clinically relevant antibiotics target the ribosome. Additionally defects in ribosome biogenesis and translation are implicated in wide variety of disease states.